Prevention of iron-mediated cytotoxicity of cultured endothelial and renal tubular epithelial cells by carnosine treatment

Epidemiological studies have indicated a positive association between high body iron stores and the risk of type 2 diabetes (T2DM). High ferritin levels in T2DM are closely related to the development of diabetic vascular complications, possibly through the interaction with VEGF. An increased transferrin excretion in diabetic patients with microalbuminuria may contribute to tubulointerstitial injuries due to transferrin reabsorption and thus increased intracellular iron concentrations in proximal tubular epithelial cells (PTEC). Because the histidine-containing dipeptide carnosine has proven its therapeutic efficacy in a variety of in vivo models for T2DM, we assessed: 1) if high glucose (HG) exposure makes cultured endothelial cells and PTEC more susceptible to metal-induced toxicity, 2) if this correlates with increased expression of known iron transporters (DMT1, IREG, TFRC), and 3) if carnosine can prevent toxicity in these cells.

Human umbilical vein endothelial cells (HUVEC) and PTEC, cultured for 2 days under normal glucose (5mM, NG) or HG (30mM), were challenged for 24h with different FeCl₃ concentrations.

Cell viability was neither impaired under HG conditions nor did HG increase susceptibility to FeCl₃. HG did not change the expression of DMT1, IREG and TFRC. L-Carnosine dose dependently abrogated toxicity regardless if the cells were cultured under NG or HG conditions.

Our data indicate that metal-induced cytotoxicity is not enhanced under HG conditions. This is compatible with an unaltered expression of the iron transporters DMT1 and TFRC. L-Carnosine displayed a strong protective effect on iron-mediated toxicity, which most likely does not involve the carnosine transporters PEPT1 or PEPT2.